Known sensors for detecting small numbers of molecules and single molecules typically require a fluorescent or metallic label. In such systems, a label is attached to the target molecule so that the target molecule can then be identified by the sensor that detects that particular label. Such labels, however, require prior knowledge of the presence of the target molecule. Thus, known sensor systems that require labels are not suitable for blind detection of target molecules that do not have labels. Further, such labels may require additional data processing. As a result, label-based detection methods and devices may not be suitable for real-time processing and are not suitable for detection of small numbers of unlabeled molecules including unlabeled single molecules.
Label-free molecule detectors have been an active research area due to the demand for reliable detection of low concentration biological agents, particularly label-free detectors for detecting small numbers of molecules and single molecules. Several devices have been proposed or utilized for label-free detection including fiber optic waveguides, nanowires, nanoparticle probes, biochips, mechanical cantilevers and micro-sphere resonators. U.S. Pat. Nos. 4,071,753 to Fulenwider et al. and 4,419,895 to Fuller describe sensors that utilize optical fibers. Another type of optical sensor involves modulation of vibrational motion of a transducer, which changes the intensity of light coupled between the ends of two optical fibers so that by measuring such changes the physical parameter can be detected and measured.
U.S. Pat. No. 6,583,399 to Painter et al. describes a micro-sphere resonant sensor that includes a modifier that is bound to an outer surface of the resonator. The modifier provides a binding site such that a binding event occurs at the outer surface of the micro-sphere in the presence of a target molecule. U.S. Publication No. 2007/0269901 A1 describes label-free sensing methods that involve a thermo-optic effect and monitoring how the resonance wavelength of the microcavity shifts when molecules bind to the outer surface of the microcavity. Molecules that bind to an outer surface of a microcavity interact with an evanescent field generated by optical energy resonating within the microcavity, thereby resulting in heating of the microcavity, which alters the index of refraction and resonance wavelength.
While certain known devices may be utilized for label-free detection, they can be improved. Certain known sensors do not have sufficient sensitivity to allow detection of a very small number of molecules or a single molecule. These low sensitivity sensors may not be suitable for biological and chemical analyses that require higher sensitivities such as cell signaling and cellular dynamics and various environmental applications. The reasons for inadequate sensitivities are specific to each type of sensor. For example, sensitivities of sensors having mechanical components may be limited given the particular mechanical construct.
Certain known devices may also have other limitations. For example, in the case of certain optical sensors and traps, sensitivity limitations are due, in part, to the limited interaction of light with the target molecule. Further, the reliability and sensitivity of other sensing methods, such as methods that monitor resonance wavelength, may be affected by the optical path fluctuation within the microcavity due to factors such as temperature variations, turbulence that is induced by injection of bio-fluids into the microcavity environment and frequency jittering of a laser source coupled to the microcavity.
Various sensors also present manufacturing and integration challenges that limit the extent to which the devices can be used on a large-scale basis. Further, in the case of optical sensors, it is necessary to increase the evanescent field intensity to increase the detection limit into the single molecule regime, but many optical sensors are not physically capable of such intensity increases.